The genus Enterococcus has been established as a separate genus from Streptococcus, based on nucleic acid hybridization studies (Schleifer, K. H. and R. Kilpper-Balz, Int. J. Syst. Bacteriol. 344:31-34 (1984)). The enterococci include the species E. faecalis, E. faecium, E. avium, E. casseliflavus, E. durans, E. gallinarum, E. malodoratus, E. raffinosus, B. pseudoavium, E. soliltarius, E. mundtii, and E. hirae (Murray, B. E., "Enterococci," pp. 1415-1420 In Gorbach, S. L., et al., eds., Infectious Diseases, W. B. Saunders Co., Harcourt Brace Jovanovich, Inc., Philadelphia, 1992).
Enterococcus faecalis and Enterococcus faecium are the two most clinically important strains of the genus Enterococcus, accounting for over 95% of all enterococcal infections. As part of the normal flora of the human bowel and genital tract, the enterococci had not been thought to cause serious infection. In recent years, however, the enterococci have emerged as clinically important pathogens responsible for 5-15% of bacterial endocarditis, 15% of intra-abdominal pelvic and wound infections, 5-10% of spontaneous peritonitis, 5-10% of nosocomial bacteremia and 15% of nosocomial urinary tract infections (ibid). Enterococcal isolates are increasingly responsible for nosocomial infections and are a common cause of morbidity and mortality. Recently they have been cited as the second most common pathogen isolated from hospitalized patients (Schaberg, D. R. et al., Am. J. Med. 91:(suppl. 3B) 72S-75S (1991)).
The increase in enterococcal disease is most likely due to an increase in the use of invasive devices, an increase in the number of seriously ill patients and an increase in the use of antimicrobial agents to which enterococci have developed resistance (Nicoletti, G. and Stefani, Eur. J. Clin. Microbiol. Infect. Dis. 14: (suppl. 1) 33S-37S (1995)).
Enterococci are intrinsically resistant to a large number of antimicrobial agents including beta lactams, polymyxins and lincosamides. In addition, many species have developed resistance to a number of other antimicrobial agents including ampicillin, aminoglycosides, chloramphenicol, erythromycin and vancomycin. Many strains of enterococci now exhibit multiple drug resistance. Some nosocomial isolates of enterococci have displayed resistance to essentially every useful antimicrobial agent, exemplifying the increased difficulty in treating and controlling enterococcal infections (Jones, R. N. et al., Diagn. Microbiol. Infect. Dis. 21:95-100 (1995); Jones, R. N. et al., Diagn. Microbiol. Infect. Dis. 21:85-93 (1995)).
The incidence of resistance to antimicrobial agents among enterococci is continuing to rise at an alarming rate. The ability of this genus to develop and acquire new resistance has lead, in some cases, to ineffective treatments with agents currently available. The development of a new generation or class of antimicrobial agent is clearly needed to solve the growing threat which enterococcal infections present.
The design of effective antibiotics should exploit the biological differences between the pathogen and host. Designing new antibiotics requires the identification of potential targets in enterococci such as Enterococcus faecalis. The search for exploitable differences in the enzymatic pathways of E. faecalis and humans is hindered by the limited understanding of the biology of enterococci.